Inflammation is key to ALS

The same immune process responsible for arthritis and juvenile diabetes
could be the one of the "hits" that contributes to the degenerative
nerve disorder amyotrophic lateral sclerosis (ALS), also known as Lou
Gehrig's disease. That process is called inflammation.

Neurologists theorize that inflammation may contribute to the disease
along with the person's genes and surrounding environment.

"In non-familial ALS, which is 90 percent of the cases with ALS,
it is likely that there is an environmental trigger for the disease,"
said Stanley Appel, M.D., chair for the department of neurology and director
of the MDA/ALS clinic at Baylor College of Medicine. "But ALS is
not that common, so that particular person also has to be sensitive to
the environmental trigger. That is what I call a minimum of a two-hit
phenomenon. You have to have both for the disease to occur." That
sensitivity could be a gene or something not yet identified.

ALS researchers are investigating the possibility that inflammation is
a "third hit" that may contribute to ALS. Damage to motor
neurons may cause the body to launch an overzealous inflammatory counter
attack, killing the motor neurons, and launching the chain reaction that
causes the degenerative disease.

Inflammation may provide answers to some puzzling questions about the
disease. Researchers have found that when they inject a mutated SOD1 gene,
associated with the killing of motor neurons, into an animal model, the
animal develops the disease. However, when the gene is injected directly
into the motor neurons, the animal does not develop the disease.

One theory about this phenomenon is that the nervous system's immune
cells called microglia are responsible for the motor neuron injury. Located
in the brain and spinal cord, microglia normally clear away dead cells
after injury and in turn attack invaders to the body like bacteria.

"So what we are saying here is if the motor neuron doesn't
die by itself, there must be accomplices responsible for killing it, and
these accomplices are part of an inflammatory reaction," Appel said.
"The inflammation is what is doing the cells in, not the original
causes."

Slight damage to the motor neuron or abnormal microglia sends signals
that start the inflammation process. "Inflammation is a community
response, and is triggered by multiple factors," Appel said. "There
are multiple blocks and checks in this system and when these blocks and
checks don't work, that's when you get the disease."

Based on the theory that a faulty immune system may contribute to ALS,
Appel together with Uday Popat, M.D., and Malcolm Brenner, MBBCH, Ph.D., at
Baylor's Center for Cell and Gene Therapy, are conducting a trial
in humans using bone marrow transplantation as a treatment for the disease.
The bone marrow in ALS patients is wiped out and replaced with bone marrow
stem cells from one of their siblings. Baylor is the only center in the
country participating in the trial. So far, six patients have had bone
marrow transplants.

"It is too early to tell how the trial is going, but we are hopeful,"
Appel said. "Two patients are doing spectacularly well. Their disease
has not progressed in seven months. You might say that two of six are
not very good odds, but, it is possible that these two might not be doing
so well without aggressive intervention. However, to be honest, these
two might also have done well without the transplant. Time will tell."

How the disease works

The degeneration occurs in the motor neurons that control communication
from the spinal cord to the muscle, called lower motor neurons,
and also from the brain to the spinal cord, called upper motor neurons.
Both upper and lower motors are necessary for muscle contraction
and movement.

Degeneration of the motor neurons leads to:

weakness,

twitching of the muscles,

muscle atrophy, stiffness,

and cramping

The disease progresses over a three to five year period in most
patients, but its progression varies from patient to patient. In
some patients, the disease progresses rapidly over a year. Other
ALS patients, like English physicist Stephen Hawking, can live for
years with the disease.

Eventually, the patient with ALS is paralyzed, and will usually
die of respiratory failure. For more information about ALS, visit
Baylor's
MDA/ALS clinic website.